In my appointment as Director of the Basel Institute for Immunology, from 1980-2001, I have selected, supported, guided, critically reviewed and integrated over 300 scientists with their research projects in most major fields of immunology, covering the innate and adaptive immune systems of many species, including human. Many of these scientists are now well-established senior members of the international community of immunologists, and molecular and cellular biologists. These scientists are the cores of a network of BII alumni.
In June 2000 Roche decided to close the Institute and to terminate my assignment as Director. I remain a professor of immunology at the University of Basel and maintain a number of visiting appointments at other academic institutions.
In December 2002I became, together with Drs. Ulf Grawunder and Dirk Haasner the Co-founderof4-Antibody, a company that intends to produce and improve human antibodies. In the fall of 2003 I accepted an offer by the Max Planck-Institute for Infection Biology to head a Senior Research Group with which I intend to continue some of the research on stem cells and B cell development.

From 1973 to 1979 I have provided the Faculty of Biology of the University of Heidelberg with lectures (50-60 hours per year) covering basic and applied immunology, as well as a three-week practical course in immunology, thereby establishing a curriculum in Immunology at the Biology Faculty. From 1980 until today I have done the same for the University of Basel. A 12-hour introductory lecture series on the basic principles and major applications of immunology was followed, on a yearly basis, by 50-60 hours of lectures and seminars in basic, applied and clinical immunology. In addition, an eight-day-long practical course in immunology was given with the course on cell biology at the Biozentrum of the University of Basel. Initially this was done together with Dr. Roland Gisler, in the last five years also with other members of the Basel Institute for Immunology. I have graduated students with work in my laboratory to Ph.D.With all these activities I have secured a curriculum in Immunology at the University of Basel.

Among the many advisory and review activities I would like to mention three in more detail.
In 1985 the Government of Berlin asked me to help in the planning of a biomedical research center for rheumatoid arthritis, hoping that the success of the Basel Institute could be transplanted to Berlin. This has led to the foundation and successful establishment of the "Deutsche Rheuma¬forschungszentrum" (DRFZ), under the past directorship of Avrion Mitchison, and the present directorship of Andreas Radbruch.The center is housed at the Charité, together with the Max Planck Institute for Infectious Biology, and is engaged in research on autoimmune diseases in close collaboration with the Chair of Rheumatology.I am a member of the Stiftungsrat of the DRFZ.
In 1990 the German Science Council (Wissenschaftsrat) asked me to participate in the review of 17 biomedically oriented institutions of the Academy of the former German Democratic Republic. As a consequence of this review, a new foundation for research in molecular medicine was proposed for the former Institutes of Molecular Genetics, Cancer and Cardiovascular Diseases in Berlin-Buch.
I became co-chairman of the founding committee, and later chairman (until 1998) of the Scientific Council of the Kuratorium of the research center, named the Max Delbrück Center for Molecular Medicine, and headed by Professor Detlev Ganten.
In 1987 the German Society for Immunology asked me to organize the scientific program of the 125 workshops and 25 symposia of the 7th International Congress of Immunology, held in Berlin in 1989 and attended by over 7000 participants active in basic, applied and clinical immunology.
As a permanent scientific member (1970-1980) and as director (1980-2001) of the Basel Institute for Immunology (which was an academically free research institute, wholly supported by F. Hoffmann-La Roche during its entire 30 years of operation) I have restricted my consultant-ships for commercial companies to giving Roche, especially in the areas of gene expression and protein production, monoclonal antibodies in diagnosis and therapy, cytokines and cytokine receptors (Il-1, TNF-a, etc.) in inflammation and autoimmune diseases, and vaccine developments, especially against influenza and malaria.

After my retirement I began consulting for law firms and biotech companies. In 2003 I became Senior Research Group Leader at the Max Planck Institute for Infection Biology, Berlin, Germany.

Alternating between the National Cancer Institute, National Institutes of Health in Betesda/MD and the Basel Institute for Immunology in Switzerland, Dr. Michael Potter and I have organized for 20 years the B cell neoplasia workshops as a forum for discussions on normal B cell development and responses, their deregulations in cancers of the B lymphocyte lineage and the steps that lead to malignant transformation of the normal cells.

My scientific interests in the laboratory have, over 35 years, been centered on B-lymphocytes in normal immune reactions, and in autoimmune, immunodeficient and malignant diseases. I have studied their development from pluripotent hematopoietic stem cells, the generation of their antibody repertoires as receptors and secreted effector molecules, the molecular mechanisms which control proliferation, allelic exclusion and antibody repertoire selection, and those which control proliferation and differentiation to Ig H chain-class-switched, hypermutated Ig-secreting plasma cells, with and without the help of T-lymphocytes.

My studies began at the end of the developmental pathway of B cells, with the biochemistry of Ig molecules in B cells and plasma cells. One major focus was the role of the carbohydrate moieties of Ig in the process of intracellular transport, surface deposition and secretion of Ig in B cells and plasma cells.

Next, the molecular status of a resting mature B cell and its change after activation was defined by cell cycle analysis, by Ig synthesis and turnover, and by reactivities to a series of polyclonal activators and cytokines. A plaque test using protein A was developed. It allowed the detection of all Ig-secreting cells resulting from polyclonal or antigen-specific stimulation as single cells. Tissue cultures in serum-free medium were perfected, so that one of three mature B cells could be stimulated to grow into a clone of proliferating, increasingly Ig-secreting cells, with cloning efficiencies near 100%. This, for the first time allowed a quantitation of B cell responses "in vitro" and "in vivo" to mitogens and to then newly available helper T cell clones. It also allowed defining B cell defects of immunodeficient and of autoimmune-prone mice, and of graft-versus-host diseased animals.

Within the last fifteen years, three seminal discoveries have been made. One is the discovery of the structure and function of the surrogate light chain in precursor B cell selection and expansion, one key molecule in B cell development of mouse, man and other species.

Two precursor B cell-specific genes, VpreB and 5 were identified which encode two polypeptide chains forming the surrogate light chain. When H chains are first expressed during B cell development a preB cell receptor of H chains with surrogate light chain can be expressed on the cell surface. Whenever that happens, the preBII cells enter between 2 and 7 divisions, forming between 4 and 100 precursor cells with the same H chain in which now L chain gene rearrangements can happen. Whether the preB cell receptor also signals, allelic exclusion remains an unsolved problem. Immunodeficiencies involving mutations in the 5 gene have been found in humans and result in similarity extensive B cell immunodeficiencies.

In the second discovery, pre-adipocytic fibroblast cell lines and recombinant IL-7 were found to allow, with 100% cloning efficiency, to clone and propagate single pre-BI cells in culture for weeks and months. This proliferative capacity of pre-BI cells has recently been tested to break the "Hayflick-barrier", since such pre-BI cells (from different strains of mice) can proliferate for at least 150 divisions. Transplantation of such wild type pre-BI cells into severe combined immunodeficient (i.e. SCID or RAG) recipients establish BI-like compartments, which can be converted to convention all B cell compartments in the host by the co-transplantation of CD4 helper T cells. The transplanted precursors do not home back to the bone marrow. The transplanted B cells are tolerant to auto-antigens of the host. In humans such transplantation should allow a selective reconstitution of the antibody-producing B cell compartments.
The transition from immature B cells in bone marrow to marrow B cells in spleen has been genetically divided into two steps: immature cell transition from bone marrow to spleen, followed by maturation in the spleen from immature to mature cells. Again, immunodeficiencies and autoimmune-prone situations have been analyzed which affect these steps of B cell development.

The third discovery led to the isolation of a multipotent, long-term reconstituting hematopoietic stem cell from PAX-5-deficient mice, which has opened new, exciting possibilities to study and to manipulate the molecular and cellular programs of development of most cells of the innate and adaptive immune system. These cells, once obtainable from humans, are likely to revolutionize the practice of bone marrow transplantation in the treatment of cancer and autoimmune diseases, and in gene therapy of hematopoietic and lymphopoietic deficiencies and deregulations.

With this work our laboratory has developed into a reference center for the analysis of B cell developmental defects in immunodeficient, autoimmune-diseased and premalignant mice, with limited application to human diseases.

Beyond my experimental scientific interests I have had the privilege to develop a comprehensive view of the immune system, not only because I have attempted to teach immunology to students, but because for twenty years, as the director of the BII, I have introduced the research projects of the fifty scientists, fifteen students and twenty visitors that were undertaken at any year at the institute. My views of the immune system during 1980-2000 can be read in the introductions to the Annual Reports of the Basel Institute for Immunology.